1. Field of the Invention
The invention is in the field of treatment and control of disorders and medical conditions associated with inappropriately high platelet activation or aggregation.
2. Description of the Related Art
Blood clotting and hemostasis are complex processes involving platelets, soluble clotting factors and tissue elements. Clotting function has been conceptually divided into platelet activity and clotting factor reactions. Platelets form an integral part of the body's capacity for hemostasis. Upon activation, platelets change shape, aggregate, and secrete their granular contents, resulting in the aggregation of platelets with each other and with non-platelet surrounding cells. The granular contents of platelets supply additional adhesion molecules, growth factors, coagulation enzymes and other specialized molecules instrumental in the process of blood coagulation and thrombus formation as well as the initiation of tissue growth and healing processes.
Many chronic and acute diseases are associated with inappropriately high platelet activity and thrombosis. A connection is also emerging between platelet activation and inflammation, particularly allergic inflammation (e.g., in asthma) and inflammation at the sites of atherosclerotic damage. See, for example: Rinder & Fitch, 1996, J Cardiovasc Pharmacol 27, Suppl. 1:S6 12 (investigating the role of complement components in activation of platelet and polymorphonuclear neutrophils by cardiopulmonary bypass); Palabrica et al., 1992, Nature 359, 848 851 (P-selectin mediates leukocyte adhesion to platelets in vivo, and the bound leukocytes promote fibrin deposition); Papayianni et al., 1995, Kidney Int 47, 1295 1302 (reduction of platelets reduces generation of immune modulator lipoxin A4 generation during experimental immune complex-mediated glomerulonephritis); Bazzoni et al., 1991, Haematologica 76, 491 499 (review describing the elaborate cross-talk between platelets and neutrophils in thrombotic and inflammatory diseases); and Kazura, 1989, J Lab Clin Med 114, 469 470 (editorial on the platelet-neutrophil interaction and modulation of the inflammatory response). Therefore, compounds that inhibit platelet activation may also be useful in the treatment or prevention of disorders involving inflammation.
There are a number of agents presently available that target platelet function, such as aspirin, which is an irreversible platelet inhibitor. In addition to the unwanted anticoagulation associated with overdosage, aspirin may cause life-threatening allergic reactions in sensitive individuals. Another platelet inhibiting agent is ticlopidine (Ticlid™, Roche Pharmaceuticals). However, because it requires the production of active metabolites to be effective, the effect of ticlopidine is delayed 24 to 48 hours and individuals lacking the appropriate cytochrome P450 enzymes necessary for the production of the active metabolites are resistant to its effects. Ticlopidine is also associated with the unwanted side effects of thrombotic thrombocytopenic purpura, a life-threatening condition, as well as nausea, abdominal pain, dyspepsia, diarrhea and skin rash. Clopidogrel (Plavix™, Bristol-Meyers Squibb/Sanofi Pharmaceuticals) is another platelet inhibitor that requires the generation of active metabolites for its therapeutic efficacy. Therefore, clopidogrel also has a delay of 24 to 48 hours for its effect. Clopidogrel is also associated with unwanted side effects such as thrombotic thrombocytopenia purpura as well as agranulocytopenia, both of which may be life-threatening conditions. In addition clopidogrel has been associated with rash, edema, hypertension, hypercholesterolemia, nausea, abdominal pain, dyspepsia, diarrhea, urinary tract infections, liver enzyme elevations and arthralgia. The platelet inhibitory agents Abciximab and c7E3 Fab (Reopro Abciximab™, manufacturer—Centocor B. V., distributor—Eli Lilly and Co.) are only available in a parenteral form. These drugs may in addition cause severe thrombocytopenia in addition to their desired anticoagulant effects. Both have a very long half-life and, therefore, complicate surgery that is sometimes required in the setting of life-threatening arterial occlusion (e.g., emergent cardiac surgery in the settings of myocardial infarction or aortic aneurism).
Eptifibatide (Integrilin™, COR Therapeutics, Inc., Key Pharmaceuticals Inc.) and Tirofiban (Aggrastat™, Merck and Co., Inc.) are additional platelet inhibitory agents that are only available in a parenteral form. Tirofiban may cause thrombocytopenia, coronary artery dissection, bradycardia and edema, as well as dizziness and vasovagal reactions. Eptifibatide may cause hypotension.
There are also antithrombotic agents which target the clotting factor based functions of coagulation. Examples include Heparin, Warfarin and Hirudin analogues. Heparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant and as an anticoagulant surface coating on the inner surfaces of various experimental and medical devices such as test tubes and renal dialysis machines to prevent blood clotting. Heparin prevents the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation in acute settings such as acute coronary syndrome, e.g., NSTEMI, Atrial fibrillation, Deep-vein thrombosis and pulmonary embolism, Cardiopulmonary bypass for heart surgery, and in ECMO circuits for extracorporeal life support. It has a distinct advantage over other agents in the acute setting due to its easy rapid reversibility with protamine sulfate. Heparin is given parenterally, as it is degraded when taken by mouth. Heparin may be injected intravenously or subcutaneously (under the skin). Intramuscular heparin injections (into muscle) are avoided because of the potential for forming hematomas. Because of its short biologic half-life of approximately one hour, heparin must be given frequently or as a continuous infusion. However, the use of low-molecular-weight heparin (LMWH) has allowed once-daily dosing, thus not requiring a continuous infusion of the drug. If long-term anticoagulation is required, heparin is often used only to commence anticoagulation therapy until the oral anticoagulant warfarin takes effect.
Hirudin, found naturally in the saliva of the medicinal leech, is an inhibitor of a specific factor in the soluble clotting factor cascade. Hirudin and its analogues have been used in medical cases requiring anticoagulation when other forms of anticoagulation are contraindicated or ineffective.
Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, Lawarin, and Waran) is an anticoagulant that acts through inhibition of clotting factor synthesis. Despite its effectiveness, treatment with warfarin has several shortcomings. It has a relatively long half-life and many commonly used medications interact with warfarin, as do some foods. Its activity has to be monitored by frequent blood testing for the international normalized ratio (INR) to ensure an adequate yet safe dose is taken since its effects require synthesis of clotting factors. Warfarin is prescribed to people with an increased tendency for thrombosis or as secondary prophylaxis (prevention of further episodes) in those individuals that have already formed a blood clot (thrombus). Warfarin treatment may help prevent formation of future blood clots and reduce the risk of embolism (migration of a thrombus to a spot where it blocks blood supply to a vital organ).
In addition to the antithrombotic agents already on the market, there is still a need in the art for additional anticoagulant and platelet inhibitory agents for the treatment and prevention of diseases or disorders characterized by inappropriately elevated platelet activation, platelet aggregation and/or thrombosis. While these diseases may respond to anticoagulant therapy, they often require rapid surgical intervention and consequently the ability to rapidly reverse the anticoagulated state is highly advantageous.